Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy.

Published

Journal Article

Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor (FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated T cell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.

Full Text

Duke Authors

Cited Authors

  • Grabner, A; Amaral, AP; Schramm, K; Singh, S; Sloan, A; Yanucil, C; Li, J; Shehadeh, LA; Hare, JM; David, V; Martin, A; Fornoni, A; Di Marco, GS; Kentrup, D; Reuter, S; Mayer, AB; Pavenstädt, H; Stypmann, J; Kuhn, C; Hille, S; Frey, N; Leifheit-Nestler, M; Richter, B; Haffner, D; Abraham, R; Bange, J; Sperl, B; Ullrich, A; Brand, M; Wolf, M; Faul, C

Published Date

  • December 1, 2015

Published In

Volume / Issue

  • 22 / 6

Start / End Page

  • 1020 - 1032

PubMed ID

  • 26437603

Pubmed Central ID

  • 26437603

Electronic International Standard Serial Number (EISSN)

  • 1932-7420

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2015.09.002

Language

  • eng

Conference Location

  • United States